December Meeting Research Articles

Prophecy or Empiricy? Clinical value of predicting vs determining genetic variant functions.

The recent explosion of epilepsy genetic testing has created challenges for interpretation of gene variants. Assessments of the functional consequences of genetic variants either by predictive or experimental strategies can contribute to estimating pathogenicity, but there is no consensus on which approach is best. The Special Interest Group on Epilepsy Genetics hosted a session during the Annual American Epilepsy Society Meeting in December 2022 to discuss this topic. The session featured a debate of the relative advantages and limitations of predicting (prophecy) versus experimentally determining (empiricism) variant function using ion channel gene variants as examples. This commentary summarizes these discussions.

Preliminary outcomes reported from three randomized controlled trials of CD19 CAR-T cell therapies in large B cell lymphoma

The first ever randomized controlled trials (RCTs) testing chimeric antigen receptor (CAR) T cell therapy against a standard of care (SOC) are to be reported at the American Society for Hematology Annual Meeting in December 2021. Based on the published abstracts, the control arms had similar outcomes between the three trials. However, results on the CAR-T cell arms differed, with two of the three trials reporting that they met their primary endpoint favoring CAR-T cell therapy.

Results from the Phase 3 DUOTM Trial: A Randomized Comparison of Duvelisib Vs Ofatumumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Results from the Phase 3 DUOTM Trial: A Randomized Comparison of Duvelisib Vs Ofatumumab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

Subimal Ghosh Receives 2020 Devendra Lal Memorial Medal

Subimal Ghosh was awarded the 2020 Devendra Lal Memorial Medal at the virtual AGU Fall Meeting in December. The medal is for “outstanding Earth and/or space sciences research by a scientist belonging to and working in a developing country.”

Kristine M. Larson Receives 2020 Charles A. Whitten Medal

Kristine M. Larson was awarded the 2020 Charles A. Whitten Medal at the virtual AGU Fall Meeting in December. The medal is for “outstanding achievement in research on the form and dynamics of the Earth and planets.”

Peter M. Shearer Receives 2020 Inge Lehmann Medal

Peter M. Shearer was awarded the 2020 Inge Lehmann Medal at the virtual AGU Fall Meeting in December. The medal is for “contributions to the understanding of the structure, composition, and dynamics of the Earth’s mantle and core.”

Claire L. Parkinson Receives the 2020 Roger Revelle Medal

Claire L. Parkinson was awarded the 2020 Roger Revelle Medal at the virtual AGU Fall Meeting in December. The medal is for “outstanding contributions in atmospheric sciences, atmosphere-ocean coupling, atmosphere-land coupling, biogeochemical cycles, climate or related aspects of the Earth system.”

Rien van Genuchten Receives 2020 Robert E. Horton Medal

Rien van Genuchten was awarded the 2020 Robert E. Horton Medal at the virtual AGU Fall Meeting in December 2020. The medal is for “outstanding contributions to hydrology.”

Tamas I. Gombosi Receives 2020 John Adam Fleming Medal

Tamas I. Gombosi was awarded the 2020 John Adam Fleming Medal at the virtual AGU Fall Meeting in December. The medal is for “original research and technical leadership in geomagnetism, atmospheric electricity, aeronomy, space physics, and/or related sciences.”

Anthony Brian Watts Receives 2020 Maurice Ewing Medal

Anthony Brian Watts was awarded the 2020 Maurice Ewing Medal at the virtual AGU Fall Meeting in December. The medal is for “significant original contributions to the ocean sciences.”

Susan L. Beck Receives 2020 Walter H. Bucher Medal

Susan L. Beck was awarded the 2020 Walter H. Bucher Medal at the virtual AGU Fall Meeting in December. The medal is for “original contributions to the basic knowledge of the crust and lithosphere.”

Inclusion in limited distribution drug network reduces time to dalfampridine access in patients with multiple sclerosis at a health-system specialty pharmacy.

BACKGROUND: Dalfampridine improves walking speed in patients with multiple sclerosis (MS), but accessing specialty medications such as dalfampridine can be hindered by insurance restrictions, high costs, and limited distribution networks (LDNs) imposed by manufacturers. Some integrated health-systems specialty pharmacies (HSSPs) embed pharmacists in clinics and dispense medications from their internal pharmacies if included within the LDN. OBJECTIVE: To assess access to dalfampridine in patients at an HSSP before and after gaining admission to the LDN. METHODS: This study was conducted at Vanderbilt Specialty Pharmacy (VSP), an integrated HSSP at Vanderbilt University Medical Center (VUMC) with 2 clinical pharmacists embedded in the MS clinic. VSP gained access to the dalfampridine LDN on May 1, 2018, at which time the embedded pharmacists began to manage the comprehensive therapy initiation process. We performed a retrospective review of adult patients with MS who were prescribed dalfampridine from March 2010 to December 2018. Eligible prescriptions were new starts (no previous use) or restarts (after previous use and discontinuation). Prescriptions were classified as pre-VSP and post-VSP, which differentiates before and after VSP gained access to dispense dalfampridine. Study outcomes were insurance approval, initiation of therapy, and time from treatment decision to medication access. We used a proportional odds logistic regression model for time to medication access using the following covariates: pre-VSP versus post-VSP time period, insurance prior authorization (PA) denied versus approved/not needed, and baseline timed 25-foot walk. RESULTS: We included 262 patients and 290 prescriptions (260 pre-VSP and 30 post-VSP). In pre-VSP and post-VSP prescriptions, 97% were approved by insurance, and 93% of patients started therapy. Median time to medication access was 22 days (IQR = 11-45) for pre-VSP prescriptions and 1 day (IQR = 0-3) for post-VSP prescriptions. In the proportional odds logistic regression model, the odds of having a longer medication access time were significantly higher for pre-VSP prescriptions (OR = 83.219, P < 0.001) and prescriptions whose PA was initially denied (OR = 9.50, P < 0.001); 25-foot walk time was not significant (OR = 0.95, P = 0.277). CONCLUSIONS: After obtaining access to dispense dalfampridine, the time to access therapy was reduced, suggesting that LDNs delay patient access to therapy at HSSPs. DISCLOSURES: No funding was provided for this study. The authors have no conflicting interests to disclose. Preliminary results have been previously presented at the American Society of Health-Systems Pharmacy Midyear Meeting in December 2019, the Vanderbilt Health Systems Specialty Pharmacy Outcomes Research Summit in August 2020, and the National Association of Specialty Pharmacy Annual Meeting in September 2020.

Rise in Stimulant Misuse Poses Treatment Conundrum

Back to table of contents Previous article Next article Clinical & ResearchFull AccessRise in Stimulant Misuse Poses Treatment ConundrumTerri D'ArrigoTerri D'ArrigoSearch for more papers by this authorPublished Online:4 Feb 2020https://doi.org/10.1176/appi.pn.2020.1b14AbstractWithout pharmacologic therapies specifically approved for stimulant use disorders, what can psychiatrists do to stem the tide of stimulant misuse and its consequences?, “For ambivalence to treatment, focus on motivational interviewing. For poor coping skills, frequent relapses, or managing cravings, try CBT,” says John Mariani, M.D.Deaths tied to stimulants are on the rise, signaling a growing crisis that may catch the country off guard, said presenters at a session at the American Academy of Addiction Psychiatry’s 30th Annual Meeting and Scientific Sessions in December.“We have a tsunami coming of stimulant abuse, and with such a focus on opioids we may be distracted,” said Thomas R. Kosten, M.D., the JH Waggoner Chair and Professor of Psychiatry, Pharmacology, Immunology, Pathology, and Neuroscience at Baylor College of Medicine in the session’s opening comments.Timothy E. Wilens, M.D., chief of the Division of Child and Adolescent Psychiatry and director of the Center for Addiction Medicine at Massachusetts General Hospital and Harvard Medical School, presented an update on trends of misuse among youth. He said that one in six high school students has taken prescription stimulants for nonmedical reasons, whether he or she had been prescribed those medications or had obtained them illicitly. Furthermore, 43% of adolescents who take prescription stimulants for medical purposes have also used the medications for nonmedical reasons. The most common reason for doing so is to help them concentrate or stay awake.“But does it really help them concentrate? No, it’s placebo effect in at least half of them. If I said I put a dose of methamphetamine in your drink this morning, you would be more awake because you expect to be,” Wilens told the audience.Wilens called attention to the alarming trend of college students taking prescription stimulants intranasally. He cited studies suggesting that although 55% of those who misuse prescription stimulants take them orally, 40% snort them, likely because it produces stronger euphoria.Misusing prescription stimulants during adolescence can have repercussions years later, including a higher risk of substance use disorders and lower educational attainment than those who do not misuse the medications, he noted.Although there are currently no FDA-approved pharmacologic treatments for stimulant use disorder, psychosocial interventions may work, said John Mariani, M.D., an associate professor of psychiatry at Columbia University and the medical director of Columbia’s outpatient substance use disorders clinic. These treatments include, among others, the following:Contingency management, which offers rewards to patients such as cash or employment to reinforce positive behaviors such as drug abstinence, clinic attendance, or medication adherence.Cognitive-behavioral therapy (CBT).Motivational interviewing, which focuses on helping patients to develop internal motivation to change behavior. 12-step programs.Family therapy.Mariani said that contingency management “works well but those with financial incentives are very rarely implemented in treatment programs. The rewards need to be meaningful [to patients].”He also addressed 12-step programs, noting that there is limited evidence such programs help patients with stimulant use disorders. “How people feel about [these programs] predicts how well they will do. It works for fewer people than CBT. However, those for whom the programs work have greater days of abstinence [than they would without participating].” Mariani noted that some psychosocial therapies are more effective at treating particular challenges faced by patients with stimulant use disorder. “For ambivalence to treatment, focus on motivational interviewing. For poor coping skills, frequent relapses, or managing cravings, try CBT.”Frances R. Levin, M.D., the Kennedy-Leavy Professor of Psychiatry at Columbia University Irving Medical Center and chief of the Division on Substance Use Disorders at New York State Psychiatric Institute at Columbia, rounded out the session with a discussion of potential pharmacologic treatments that are being investigated, and emphasized the need for more dedicated research.“We often get within two feet of the finish line and give up, and we need to finish these clinical trials,” Levin said.That said, there are several promising candidates, according to Levin. These include dextroamphetamine sustained release for stimulant use disorder, modafinil for cocaine use disorder, bupropion for methamphetamine dependence, topiramate for cocaine use disorder with comorbid alcohol use disorder, and oral naltrexone for amphetamine use disorder.“We’ve come a long way and I don’t think we have to have a sense of nihilism that there are no medications with potential,” Levin said. ■ ISSUES NewArchived

Perceptions of Community Hematologists/Oncologists on Barriers to Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Diffuse Large B-Cell Lymphoma

Introduction The ASH Annual Meeting is a venue for presentation of outcomes data from key clinical trials in hematologic malignancies and novel drug classes used to treat them. The approval of two CAR-T therapies, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tis-cel), in the treatment of large B-cell lymphoma (LBCL), including diffuse LBCL (DLBCL), has ushered in a new class of drugs, i.e. cellular therapy. At ASH 2018, Nastoupil et al. presented data from a retrospective analysis of the characteristics and outcomes of patients with relapsed/refractory LBCL, including DLBCL, treated with commercially available axi-cel CAR-T therapy at academic centers in the United States (Nastoupil LJ, et al. Blood. 2018;132[Suppl 1]:91). The authors found that early outcomes of real-world patients receiving axi-cel therapy were comparable to those observed in the clinical trial population, despite &gt;40% of these patients failing to meet the clinical trial eligibility criteria. At a live meeting in February 2019, we sought the perceptions of community hematologists and oncologists (H/O) regarding their use of, referrals for and barriers to CAR-T therapy as well their perception of the value of the real-world evidence (RWE) presented. Methods A live meeting in February 2019 convened H/O with geographic representation from across the United States. The participants were shown data from selected oral and/or poster presentations from the 2018 ASH Annual Meeting and responded to questions regarding their perceptions of the data and its potential impact on current practice. Participants submitted their demographic responses via a web-based survey prior to the meeting and data impression responses via an audience response system at the live meeting. Results Among the 59 H/O who participated in this live market research program on February 22-23, 2019, 61% identified their primary specialty as hematology/oncology and 34% medical oncology. Only 27% of H/O had attended the 60th ASH Annual Meeting in December 2018. The participants were mostly community-based physicians, 50% in private community and 45% in community practices owned by a hospital or academic center. One-third have been in practice for over 20 years, one-third for 11-20 years and one-third for 10 or fewer years. This group sees an average of 20+ patients per day and reported B-cell non-Hodgkin lymphoma as one of the three most common hematologic malignancy they managed. 28% of H/O indicated that they have referred one patient and 24% have referred 2-5 patients for CAR-T therapy since the first approval on August 30, 2017. Of those H/O who had referred patients for CAR-T therapy, 45% indicated that none of their patients had yet received the infusion. The top two barriers to prescribing/recommending CAR-T therapy, as reported by the H/O, were the cumbersome logistics of administering therapy and following patients (52%), and the cost of the therapy (46%). Other concerns included high toxicity (24%) and lack of long-term survival data (19%), but not lack of knowledge of CAR-T therapy (2%). Furthermore, 87% of H/O agreed with the assertion that due to the limitations of randomized clinical trials, RWE is necessary to inform clinical practice. After review of the information presented on the real-world use of axi-cel, 73% of H/O indicated that this information is likely to cause them to recommend CAR-T therapy for more of their patients with DLBCL. Conclusions There is significant interest in adopting and using CAR-T therapies in LBCL amongst community H/O. This group does not perceive itself as lacking in knowledge regarding CAR-T therapy. The significant barriers of logistics and cost are potential deterrents to appropriate use. These results can inform stakeholders (manufacturers, payers, hospitals and practices) regarding the need to improve processes and develop payment models to address cost in order to facilitate access of these agents to the appropriate patients. RWE is viewed favorably by the vast majority of community H/O to inform clinical practice, due to the limitations of randomized clinical trials. Disclosures Gajra: Cardinal Health: Employment. Sweat:Cardinal Health: Employment. Jeune-Smith:Cardinal Health: Employment. Kish:Cardinal Health: Employment. Feinberg:Cardinal Health: Employment.

Gaddum Memorial Lecture 2014: receptors as an evolving concept: from switches to biased microprocessors.

This review is based on the JR Vane Medal Lecture presented at the BPS Winter Meeting in December 2014 by T. Kenakin. A recording of the lecture is included as supporting information and can also be viewed online here: https://www.youtube.com/watch?v=xrP81AQ8l-8. Pharmacological models used to describe drug agonism and antagonism have evolved over the past 20 years from a parsimonious model describing single active and inactive receptor states to models of multiconformational receptor systems modified by ligand conformational selection. These latter models describe the observed, presently underexploited, pharmacological mechanism of ligand-directed biased signalling. Biased signals can be quantified with transduction coefficients (ΔΔLog(τ/KA) values), a scale grounded in the Black/Leff operational model; this enables the optimization of biased profiles through medicinal chemistry. The past decades have also brought the availability of new technologies to measure multiple functional effects mediated by seven transmembrane receptors. These have confirmed that drugs can have many efficacies, which may be collaterally linked, that is there is no linear sequence of activities required. In addition, new functional screening assays have introduced increasing numbers of allosteric ligands into drug discovery. These molecules are permissive (they do not necessarily preclude endogenous signalling in vivo); therefore, they may allow better fine tuning of pathological physiology. The permissive quality of allosteric ligands can also change the quality of endogenous signalling efficacy ('induced bias') as well as the quantity of signal; in this regard, indices related to ΔΔLog(τ/KA) values (namely ΔLog(αβ) values) can be used to quantify these effects for optimization in the drug discovery process. All of these added scales of drug activity will, hopefully, allow better targeting of candidate molecules towards therapies.

Mixed lineage rearranged leukaemia

The purpose of this study is to explore the recent advances in understanding the pathogenesis of leukaemias with a translocation involving the mixed lineage leukaemia (MLL) gene and therapeutic implications of these discoveries. The pathogenesis of MLL-rearranged leukaemias has recently been elucidated in a flurry of clinical studies that have appeared over the past 5 years. On the basis of these studies, a phase 1 clinical trial has been initiated targeting the histone methyltransferase DOT1L with interim clinical results reported at the American Society of Hematology Annual Meeting in December 2014. Acute leukaemia, both myeloid and lymphoid, that harbours a translocation involving the MLL gene at chromosome locus 11q23 has a poor prognosis, even with allogeneic bone marrow transplantation. The pathogenesis of MLL translocated leukaemias has recently been linked to aberrant activity of the histone methyltransferase DOT1. Preclinical studies of DOT1L inhibition with potent, selective inhibitors have shown successful eradication of the leukaemic clone in animal models. On the basis of these studies, a phase 1, first in man, clinical trial has been initiated with a DOT1L inhibitor, EPZ-5676.

Localization of α-adrenoceptors: JR Vane Medal Lecture.

This review is based on the JR Vane Medal Lecture presented at the BPS Winter Meeting in December 2011 by J.C. McGrath. A recording of the lecture is included as supporting information. It covers his laboratory's work from 1990 to 2010 on the localization of vascular α1 -adrenoceptors in native tissues, mainly arteries. (i) α1 -adrenoceptors are present on several cell types in arteries, not only on medial smooth muscle, but also on adventitial, endothelial and nerve cells; (ii) all three receptor subtypes (α1 A , α1 B , α1 D ) are capable of binding ligands at the cell surface, strongly indicating that they are capable of function and not merely expressed. (iii) all of these cell types can take up an antagonist ligand into the intracellular compartments to which endocytosing receptors move; (iv) each individual subtype can exist at the cell surface and intracellularly in the absence of the other subtypes. As functional pharmacological experiments show variations in the involvement of the different subtypes in contractions of different arteries, it is concluded that the presence and disposition of α1 -adrenoceptors in arteries is not a simple guide to their involvement in function. Similar locations of the subtypes, even in different cell types, suggest that differences between the distribution of subtypes in model systems do not directly correlate with those in native tissues. This review includes a historical summary of the alternative terms used for adrenoceptors (adrenergic receptors, adrenoreceptors) and the author's views on the use of colours to illustrate different items, given his partial colour-blindness.

Meeting the Needs of the People: Fish Consumption Rates in the Pacific Northwest

Meeting the Needs of the People: Fish Consumption Rates in the Pacific Northwest

Pluripotent and Somatic Stem Cells: From Basic Science to Utilization in Disease Modeling and Therapeutic Application

Cellular ReprogrammingVol. 15, No. 5 Meeting ReportPluripotent and Somatic Stem Cells: From Basic Science to Utilization in Disease Modeling and Therapeutic ApplicationMeeting Report on the 7th International Meeting of the Stem Cell Network North Rhine WestphaliaStefan Radtke and Peter A. HornStefan RadtkeSearch for more papers by this author and Peter A. HornSearch for more papers by this authorPublished Online:27 Sep 2013https://doi.org/10.1089/cell.2013.0044AboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byFrom Stem Cell Research to Three-Dimensional Organoids and Their Applications in Cancer Research: Meeting Report on the 9th International Meeting of the Stem Cell Network North Rhine Westphalia Samantha Langer, Peter A. Horn, and Stefan Heinrichs1 October 2017 | Cellular Reprogramming, Vol. 19, No. 5From Basic Biology to Engineering and Clinical Translation of Stem Cells: Meeting Report on the 8th International Meeting of the Stem Cell Network North Rhine Westphalia10 December 2015 | Cellular Reprogramming, Vol. 17, No. 6 Volume 15Issue 5Oct 2013 InformationCopyright 2013, Mary Ann Liebert, Inc.To cite this article:Stefan Radtke and Peter A. Horn.Pluripotent and Somatic Stem Cells: From Basic Science to Utilization in Disease Modeling and Therapeutic Application.Cellular Reprogramming.Oct 2013.394-396.http://doi.org/10.1089/cell.2013.0044Published in Volume: 15 Issue 5: September 27, 2013Online Ahead of Print:September 10, 2013PDF download

The Emerging 'Post-Doha' Agenda and the New Regionalism in the Asia-Pacific

This paper considers emerging commercial policy challenges facing the Asia-Pacific region in light of the impasse reached at the Eighth World Trade Organization (WTO) Ministerial Meeting in December 2011. It underscores that, while marginal liberalization of trade barriers under the Doha Development Agenda may not be forthcoming in the short- or even medium-term, the WTO has been successful in erecting a rules-based system of global governance and continues to be extremely important to the future health of the international trading system. Nevertheless, one can expect the current trend toward bilateral and regional free-trade areas (FTAs) will continue, particularly since it is easier to make progress toward 'deep integration' in a smaller group of like-minded countries than in the context of the general WTO membership.